Abstract
Prominin-1 (CD133) is a commonly used cancer stem cell marker in central nervous system (CNS) tumors including glioblastoma (GBM). Expression of Prom1 in cancer is thought to parallel expression and function in normal stem cells. Using RNA in situ hybridization and antibody tools capable of detecting multiple isoforms of Prom1, we find evidence for two distinct Prom1 cell populations in mouse brain. Prom1 RNA is first expressed in stem/progenitor cells of the ventricular zone in embryonic brain. Conversely, in adult mouse brain Prom1 RNA is low in SVZ/SGZ stem cell zones but high in a rare but widely distributed cell population (Prom1hi). Lineage marker analysis reveals Prom1hi cells are Olig2+Sox2+ glia but Olig1/2 knockout mice lacking oligodendroglia retain Prom1hi cells. Bromodeoxyuridine labeling identifies Prom1hi as slow-dividing distributed progenitors distinct from NG2+Olig2+ oligodendrocyte progenitors. In adult human brain, PROM1 cells are rarely positive for OLIG2, but express astroglial markers GFAP and SOX2. Variability of PROM1 expression levels in human GBM and patient-derived xenografts (PDX) – from no expression to strong, uniform expression – highlights that PROM1 may not always be associated with or restricted to cancer stem cells. TCGA and PDX data show that high expression of PROM1 correlates with poor overall survival. Within proneural subclass tumors, high PROM1 expression correlates inversely with IDH1 (R132H) mutation. These findings support PROM1 as a tumor cell-intrinsic marker related to GBM survival, independent of its stem cell properties, and highlight potentially divergent roles for this protein in normal mouse and human glia.
Highlights
Prominin-1 (Prom1, PROM1, CD133) is a pentaspan transmembrane glycoprotein originally identified in immature hematopoietic cells [1,2] and widely regarded as a marker of normal and cancerous stem cells in the central nervous system (CNS) [3,4,5,6,7]
We performed an RNA in situ hybridization (RISH) study of mouse development using a mouse Prom1 probe derived from the open reading frame (ORF) of the Prom1 gene [28] to detect as many splice variants as possible
Prom1 was expressed in all ventricular zone regions of the central nervous system from E12.5–18.5 (Fig. 1A–a,b)
Summary
Prominin-1 (Prom, PROM1, CD133) is a pentaspan transmembrane glycoprotein originally identified in immature hematopoietic cells [1,2] and widely regarded as a marker of normal and cancerous stem cells in the central nervous system (CNS) [3,4,5,6,7]. Prominin-1 expression has been reported in oligodendroglia, ependymal cells, and in the human fetal spinal cord [810]. PROM1 cells isolated from the human fetal ventricular zone have the ability to generate neurospheres, which retain selfrenewal and multi-lineage differentiation capacity [9]. The distribution and characteristics of Prominin-1 cells are less well studied. In transgenic Prom1-lacZ mice, Prom1/lacZ was co-expressed with Gfap in cells of the subventricular zone (SVZ) having properties of multi-potent self-renewing neural stem cells. Prom1/ lacZ+Gfap- cells single-sorted from this region were not able to form secondary neurospheres or to differentiate into all neural lineages. LacZ expression was noted in cells with non-stem cell phenotypes widely throughout the adult mouse brain in regions but whether the endogenous gene is expressed in a similar pattern was not fully established [5,12]
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